rs139557408

Variant names:

• chr17-78125841-C-T
• rs139557408
• NM_001127198.5:c.315G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001127198.5(TMC6):​c.315G>A​(p.Thr105Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,552,718 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (4 hom.)
• Consequence: TMC6 NM_001127198.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.79
• Publications: 2 publications found

Genes affected

TMC6 (HGNC:18021): (transmembrane channel like 6) Epidermodysplasia verruciformis (EV) is an autosomal recessive dermatosis characterized by abnormal susceptibility to human papillomaviruses (HPVs) and a high rate of progression to squamous cell carcinoma on sun-exposed skin. EV is caused by mutations in either of two adjacent genes located on chromosome 17q25.3. Both of these genes encode integral membrane proteins that localize to the endoplasmic reticulum and are predicted to form transmembrane channels. This gene encodes a transmembrane channel-like protein with 10 transmembrane domains and 2 leucine zipper motifs. [provided by RefSeq, Jul 2008]

TMC6 Gene-Disease associations (from GenCC):

• epidermodysplasia verruciformis, susceptibility to, 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• epidermodysplasia verruciformis

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

ENSG00000309534 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 17-78125841-C-T is Benign according to our data. Variant chr17-78125841-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 456015.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0012 (183/152306) while in subpopulation NFE AF = 0.00212 (144/68014). AF 95% confidence interval is 0.00184. There are 0 homozygotes in GnomAd4. There are 80 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC6	NM_001127198.5	c.315G>A	p.Thr105Thr	synonymous_variant	Exon 5 of 20	ENST00000590602.6	NP_001120670.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC6	ENST00000590602.6	c.315G>A	p.Thr105Thr	synonymous_variant	Exon 5 of 20	2	NM_001127198.5	ENSP00000465261.1

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 183 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00212

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000955 AC: 151 AN: 158150 AF XY: 0.000910

Gnomad AFR exome AF: 0.000793

Gnomad AMR exome AF: 0.000200

Gnomad ASJ exome AF: 0.000235

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000259

Gnomad NFE exome AF: 0.00211

Gnomad OTH exome AF: 0.000225

GnomAD4 exome AF: 0.00198 AC: 2772 AN: 1400412 Hom.: 4 Cov.: 33 AF XY: 0.00198 AC XY: 1367 AN XY: 691042

African (AFR) AF: 0.000568 AC: 18 AN: 31666

American (AMR) AF: 0.000139 AC: 5 AN: 36012

Ashkenazi Jewish (ASJ) AF: 0.000238 AC: 6 AN: 25188

East Asian (EAS) AF: 0.00 AC: 0 AN: 35890

South Asian (SAS) AF: 0.0000504 AC: 4 AN: 79376

European-Finnish (FIN) AF: 0.000247 AC: 12 AN: 48504

Middle Eastern (MID) AF: 0.00369 AC: 21 AN: 5698

European-Non Finnish (NFE) AF: 0.00240 AC: 2597 AN: 1080022

Other (OTH) AF: 0.00188 AC: 109 AN: 58056

GnomAD4 genome AF: 0.00120 AC: 183 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.00107 AC XY: 80 AN XY: 74468

African (AFR) AF: 0.000722 AC: 30 AN: 41562

American (AMR) AF: 0.000196 AC: 3 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00212 AC: 144 AN: 68014

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00164 Hom.: 0

Bravo AF: 0.00117

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epidermodysplasia verruciformis Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.1
DANN	Benign	0.84
PhyloP100		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs139557408; hg19: chr17-76121922;